rs372153489
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_016932.5(SIX2):c.707C>T(p.Pro236Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000307 in 1,613,892 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_016932.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000217 AC: 33AN: 152250Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000244 AC: 61AN: 250282Hom.: 1 AF XY: 0.000214 AC XY: 29AN XY: 135358
GnomAD4 exome AF: 0.000316 AC: 462AN: 1461642Hom.: 1 Cov.: 31 AF XY: 0.000316 AC XY: 230AN XY: 727084
GnomAD4 genome AF: 0.000217 AC: 33AN: 152250Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15AN XY: 74372
ClinVar
Submissions by phenotype
not provided Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 236 of the SIX2 protein (p.Pro236Leu). This variant is present in population databases (rs372153489, gnomAD 0.04%). This missense change has been observed in individual(s) with congenital anomalies of the kidney and urinary tract (PMID: 27657687, 32164334). ClinVar contains an entry for this variant (Variation ID: 224349). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
SIX2-related disorder Uncertain:1
The SIX2 c.707C>T variant is predicted to result in the amino acid substitution p.Pro236Leu. This variant was reported in an individual with congenital anomalies of kidney and urinary tract (Table S3, Ahn et al. 2020. PubMed ID: 32164334). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygote. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Congenital anomaly of kidney and urinary tract Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at